Benzimidazole Derivatives

Abstract

The invention relates to a compound of formula (I) wherein R.sup.1-R.sup.3 are as defined in the description and in the claims The compound of formula (I) can be used as a medicament.

##STR00001##

Claims

1. A compound of formula (I) ##STR00022## wherein R.sup.1 is phenyl, alkylcarbonylaminoalkyl, alkylsulfonylaminoalkyl, halophenylalkyl, pyridinylalkyl, dialkylaminoalkyl, alkoxyalkyl, cycloalkyl, alkyl, haloalkyl or phenylalkyl; R.sup.2 is hydrogen or halogen; and R.sup.3 is halogen; or a pharmaceutically acceptable salt or ester thereof.

2. A compound according to claim 1, wherein R.sup.1 is phenylalkyl;

3. A compound according to claim 1 or 2, wherein R.sup.1 is phenylmethyl or phenylethyl;

4. A compound according to any one of claims 1 to 3, wherein R.sup.2 is hydrogen;

5. A compound according to any one of claims 1 to 4 , wherein R.sup.3 is chlorine;

6. A compound according to any one of claims 1 to 5 selected from 5-(2-chloro-4-methylphenyl)-1-phenyl-1H-benzo[d]imidazole-7-carboxylic acid; 1-(3 -acetamidopropyl)-5 -(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole carboxylic acid; 5-(2-chloro-4-methylphenyl)-1-(3-(methylsulfonamido)propyl)-1H-benzo[d]imidazole-7-carboxylic acid; 5-(2-chloro-4-methylphenyl)-1-(3-chlorobenzyl)-1H-benzo[d]imidazole-7-carboxylic acid; 5-(2-chloro-4-methylphenyl)-1-(pyridin-4-ylmethyl)-1H-benzo[d]imidazole-7-carboxylic acid; 5-(2-chloro-4-methylphenyl)-1-(pyridin-3-ylmethyl)-1H-benzo[d]imidazole-7-carboxylic acid; 6-(2-chloro-4-methylphenyl)-3 -(pyridin-2-ylmethyl)benzimidazole-4-carboxylic acid; 5-(2-chloro-4-methylphenyl)-1-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazole-7-carboxylic acid; 5-(2-chloro-4-methylphenyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-7-carboxylic acid; 5-(2-chloro-4-methylphenyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylic acid; 5-(2-chloro-5-fluoro-4-methylphenyl)-1-ethyl-1H-benzo[d]imidazole-7-carboxylic acid; 5 -(2-chloro-4-methylphenyl)-1-ethyl-1H-benzo[d]imidazole-7-carboxylic acid; 5-(2-chloro-4-methylphenyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-7-carboxylic acid; 5-(2-chloro-4-methylphenyl)-1-phenethyl-1H-benzo[d]imidazole-7-carboxylic acid; and 1-benzyl-5-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-7-carboxylic acid; or a pharmaceutically acceptable salt or ester thereof.

7. A compound according to any one of claims 1 to 6 selected from 5-(2-chloro-4-methylphenyl)-1-phenethyl-1H-benzo[d]imidazole-7-carboxylic acid; and 1-benzyl-5-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-7-carboxylic acid; or a pharmaceutically acceptable salt or ester thereof.

8. A process for the preparation of a compound according to any one of claims 1 to 7, comprising the saponification of a compound (A1): ##STR00023## in the presence of a base or an acid; wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in any one of claims 1 to 7 and R.sup.4 is alkyl.

9. A compound according to any one of claims 1 to 7, when manufactured according to a process of claim 8.

10. A compound according to any one of claims 1 to 7 for use as therapeutically active sub stance.

11. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 7 and a therapeutically inert carrier.

12. The use of a compound according to any one of claims 1 to 7 for the treatment or prophylaxis of systemic lupus erythrematosus (SLE), cutaneous skin diseases like dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutieres syndrome (AGS).

13. The use of a compound according to any one of claims 1 to 7 for the preparation of a medicament for the treatment or prophylaxis of systemic lupus erythrematosus (SLE), cutaneous skin diseases like dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutieres syndrome (AGS).

14. A compound according to any one of claims 1 to 7 for use in the treatment or prophylaxis of systemic lupus erythrematosus (SLE), cutaneous skin diseases like dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutieres syndrome (AGS).

15. A method for the treatment or prophylaxis of systemic lupus erythrematosus (SLE), cutaneous skin diseases like dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutieres syndrome (AGS), which method comprises administering an effective amout of a compound as defined in any one of claims 1 to 7 to a patient in need thereof.

16. The invention as hereinbefore described.

Description

EXAMPLES

[0093] Abbreviations

[0094] DCM=dichloromethane; DIPEA=diisopropylethylamine; DMSO=dimethyl sulfoxide; ESI=electrospray ionization; EtOAc=ethyl acetate; MeOH=methanol; MS=mass spectrometry; RT=room temperature; THF=tetrahydrofuran.

Example 1

5-(2-Chloro-4-methylphenyl)-1-phenyl-1H-benzo[d]imidazole-7-carboxylic acid

[0095] ##STR00007##

[0096] a) Methyl 5-bromo-3-nitro-2-(phenylamino)benzoate

[0097] In a 25 ml vial, methyl 5-bromo-2-fluoro-3-nitrobenzoate (1 g, 3.6 mmol, Eq: 1) was combined with dimethylformamide (10 ml). Aniline (1.07 g, 1.05 ml, 11.5 mmol, Eq: 3.2) was added, the vial was closed and heated to 110° C. for 1 h. The crude reaction mixture was concentrated in vacuo, poured into 100 ml 2M HCl and extracted with EtOAc (3×150 ml). The organic layers were combined, dried over MgSO.sub.4, filtered through sintered glass, concentrated and dried in vacuo. The crude material was purified by chromatography (silica gel, 40 g, 0% to 40% EtOAc in heptane) to afford the title compound methyl 5-bromo-3-nitro-2-(phenylamino)benzoate (1.11 g, 3.13 mmol, 87.1% yield) as red solid, MS (ESI): 352.96 [M+H]+.

[0098] b) Methyl 2′-chloro-4′-methyl-5-nitro-4-(phenylamino)-[1,1′-biphenyl]-3-carboxylate

[0099] To methyl 5-bromo-3-nitro-2-(phenylamino)benzoate (500 mg, 1.42 mmol, Eq: 1) in dioxane (8 ml) was added (2-chloro-4-methylphenyl)boronic acid (243 mg, 1.42 mmol, Eq: 1). Potassium phosphate (604 mg, 2.85 mmol, Eq: 2) dissolved in water (2 ml) was added. The mixture was degassed during 2 min before X-Phos (33.9 mg, 71.2 μmol, Eq: 0.05) and tris(dibenzylideneacetone)dipalladium-chloroform adduct (36.8 mg, 35.6 μmol, Eq: 0.025) were added. The mixture was heated to 110° C. for 2 hours. The reaction mixture was poured into 100 ml of water and extracted with EtOAc (3×100 ml). The organic layers were dried over MgSO.sub.4 and concentrated in vacuo. The crude material was purified by chromatography (silica gel, 80 g, 0% to 30% EtOAc in heptane) to afford the title compound methyl 2′-chloro-4′-methyl-5-nitro-4-(phenylamino)-[1,1′-biphenyl]-3-carboxylate (520 mg, 966 μmol, 67.9% yield) as red solid, MS (ESI): 397.14 [M+H]+.

[0100] c) Amino-2′-chloro-4′-methyl-4-(phenylamino)-[1,1′-biphenyl]-3-carboxylate

[0101] In a 25 ml round-bottomed flask, methyl 2′-chloro-4′-methyl-5-nitro-4-(phenylamino)-[1,1′-biphenyl]-3-carboxylate (450 mg, 1.13 mmol, Eq: 1) was combined with ethyl acetate (9 ml). The air was replaced several times with argon before Pd-C (54.3 mg, 51 μmol, Eq: 0.045) was added, then argon was replaced several times with H.sub.2. The reaction was stirred at room temperature overnight. For work-up H.sub.2 was exchanged with argon and the reaction was filtered. The solution was concentrated and the residue dried in vacuo. The crude material was purified by chromatography (silica gel, 12 g, 0% to 50% EtOAc in heptane) to afford the title compound methyl 5-amino-2′-chloro-4′-methyl-4-(phenylamino)-[1,1′-biphenyl]-3-carboxylate (306 mg, 763 μmol, 67.2% yield) as light yellow solid, MS (ESI): 367.18 [M+H]+.

[0102] d) Methyl 5-(2-chloro-4-methylphenyl)-1-phenyl-1H-benzo[d]imidazole-7-carboxylate

[0103] In a 10 ml round-bottomed flask, methyl 5-amino-2′-chloro-4′-methyl-4-(phenylamino)-[1,1′-biphenyl]-3-carboxylate (50 mg, 136 μmol, Eq: 1) and formic acid (627 mg, 523 μl, 13.6 mmol, Eq: 100) were combined. The reaction mixture was heated to reflux for 5 min, then poured slowly into 20 ml saturated NaHCO3 solution and extracted with EtOAc (3×25 ml). The organic layers were combined, dried over MgSO4, filtered through sintered glass, concentrated and dried in vacuo. The crude material was purified by chromatography (silica gel, 12 g, 0% to 50% EtOAc in heptane) to obtain the title compound methyl 5-(2-chloro-4-methylphenyl)-1-phenyl-1H-benzo[d]imidazole-7-carboxylate (34 mg, 83 μmol, 60.9% yield) as white solid, MS (ESI): 377.15 [M+H]+.

[0104] e) 5-(2-Chloro-4-methylphenyl)-1-phenyl-1H-benzo[d]imidazole-7-carboxylic acid

[0105] To a solution of methyl 5-(2-chloro-4-methylphenyl)-1-phenyl-1H-benzo[d]imidazole-7-carboxylate (26.6 mg, 70.6 μmol, Eq: 1) in THF (700 μl) was added LiOH (5.92 mg, 141 mol, Eq: 2) dissolved in water (350 μl). The reaction mixture was heated to 65° C. and stirred until completion of the reaction. The reaction was quenched with HCl (70.6 μl, 141 μmol, Eq: 2), 15 ml of water was added and the mixture was extracted with EtOAc (3×25 ml). The organic layers were combined, dried over MgSO4, filtered through sintered glass, concentrated and dried in vacuo. The crude material was purified by chromatography (silica gel, 12 g, 0% to 100% EtOAc in heptane and then 0-7% MeOH in DCM to afford the title compound 5-(2-chloro-4-methylphenyl)-1-phenyl-1H-benzo[d]imidazole-7-carboxylic acid (15 mg, 38.8 μmol, 55% yield) as white solid, MS (ESI): 363.16 [M+H]+.

Example 2

1-(3-Acetamidopropyl)-5-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-7-carboxylic acid

[0106] ##STR00008##

[0107] a) Methyl 6-bromo-1H-benzo[d]imidazole-4-carboxylate

[0108] In a 250 ml round-bottomed flask, 6-bromo-1H-benzo[d]imidazole-4-carboxylic acid (2.9 g, 12 mmol, Eq: 1) was combined with methanol (100 ml) to give a light brown suspension. Sulfuric acid (11.8 g, 6.41 ml, 120 mmol, Eq: 10) was added at 0° C. The reaction mixture was heated to 65° C. and stirred overnight. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 100 ml of saturated NaHCO.sub.3 solution and extracted with EtOAc (3×150 ml). The organic layers were combined, dried over MgSO.sub.4, filtered through sintered glass, concentrated and dried in vacuo to afford the title compound methyl 6-bromo-1H-benzo[d]imidazole-4-carboxylate (1.97 g, 7.63 mmol, 63.5% yield) as off-white solid, MS (ESI): 255.04, 257.05 [M+H]+.

[0109] b) Methyl 6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate

[0110] In a 100 ml round-bottomed flask, methyl 6-bromo-1H-benzo[d]imidazole-4-carboxylate (2 g, 7.84 mmol, Eq: 1), (2-chloro-4-methylphenyl)boronic acid (1.34 g, 7.84 mmol, Eq: 1) and potassium phospohate (tribasic) (3.33 g, 15.7 mmol, Eq: 2) were combined with dioxane (40 ml) and water (10 ml). Under argon tris(dibenzylideneacetone)dipalladium-chloroform adduct (203 mg, 196 μmol, Eq: 0.025) and X-phos (187 mg, 392 μmol, Eq: 0.05) were added. The reaction was heated to 100° C. and stirred for 4 h. The reaction mixture was poured into 50 ml of saturated NaHCO.sub.3 solution and extracted with EtOAc (3×100 ml). The organic layers were combined, dried over MgSO.sub.4, filtered through sintered glass, concentrated and dried in vacuo. The crude material was purified by chromatography (silica gel, 80 g, 0% to 80% EtOAc in heptane to afford the title compound methyl 6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate (852 mg, 2.69 mmol, 68.6% yield) as white solid, MS (ESI): 301.12 [M+H]+.

[0111] c) Methyl 1-(3-((tert-butoxycarbonyl)amino)propyl)-5-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-7-carboxylate

[0112] In a 50 ml round-bottomed flask, methyl 6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate (780 mg, 2.46 mmol, Eq: 1) and cesium carbonate (1.27 g, 3.89 mmol, Eq: 1.58) were combined with dimethylformamide (20 ml). tert-butyl (3-bromopropyl)carbamate (927 mg, 3.89 mmol, Eq: 1.58) was added and the reation was stirred at room temperature overnight. The reaction mixture was poured into 150 ml of saturated NaCl solution and extracted with EtOAc (3×200 ml). The organic layers were combined, dried over MgSO.sub.4, filtered through sintered glass, concentrated and dried in vacuo. The crude material was purified by chromatography (silica gel, 40 g, 0% to 100% EtOAc in heptane to afford the title compound methyl 1-(3-((tert-butoxycarbonyl)amino)propyl)-5-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole carboxylate (571 mg, 1.25 mmol, 50.6% yield) as off-white solid, MS (ESI): 458.185 [M+H]+.

[0113] d) Methyl 1-(3-aminopropyl)-5-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-7-carboxylate hydrochloride

[0114] In a 25 ml round-bottomed flask, methyl 1-(3-((tert-butoxycarbonyl)amino)propyl)-5-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-7-carboxylate (571 mg, 1.25 mmol, Eq: 1) and HCl in dioxane (1.56 ml, 6.23 mmol, Eq: 5) were combined with dioxane (8 ml). The reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo to afford the title compound methyl 1-(3-aminopropyl)-5-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-7-carboxylate hydrochloride (315 mg, 880 μmol, 70.6% yield) as white foam which was used in the next step.

[0115] e) Methyl 1-(3-acetamidopropyl)-5-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-7-carboxylate

[0116] In a 5 ml round-bottomed flask, methyl 1-(3-aminopropyl)-5-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-7-carboxylate (60 mg, 168 μmol, Eq: 1) and DIPEA (65 mg, 87.9 μl, 503 μmol, Eq: 3) were combined with dichloromethane (2 ml). At 0° C. acetyl chloride (14.5 mg, 13.1 μl, 184 μmol, Eq: 1.1) was added. The reaction was stirred for 1 h at room temperature. The reaction mixture was poured into 20 ml saturated NaHCO.sub.3 solution and extracted with EtOAc (3×25 ml). The organic layers were combined, dried over MgSO.sub.4, filtered through sintered glass, concentrated and dried in vacuo. The crude material was purified by chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM to afford the title compound methyl 1-(3-acetamidopropyl)-5-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-7-carboxylate (17.7 mg, 42.2 μmol, 25.2% yield) as white solid, MS (ESI): 400.25 [M+H]+.

[0117] f) 1-(3-Acetamidopropyl)-5-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-7-carboxylic acid

[0118] To a light yellow solution of methyl 1-(3-acetamidopropyl)-5-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-7-carboxylate (17.7 mg, 44.3 μmol, Eq: 1) in tetrahydrofuran (500 μl) was added lithium hydroxide monohydrate (3.71 mg, 88.5 μmol, Eq: 2) dissolved in water (250 μl). The mixture was heated to 65° C. and stirred overnight. The mixture was concentrated in vacuo. The residue was taken up with methyltetrahydrofuran (2 ml) and the formed crystals were filtered through a Sartorius funnel to obtain the title compound 1-(3-acetamidopropyl)-5-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-7-carboxylic acid (17.9 mg, 44.3 μmol, 100% yield) as an off-white solid, MS (ESI): 386.14 [M+H]+.

Example 3

5-(2-Chloro-4-methylphenyl)-1-(3-(methylsulfonamido)propyl)-1H-benzo[d]imidazole-7-carboxylic acid

[0119] ##STR00009##

[0120] The title compound was obtained in comparable yield analogous to the procedure described for Example 2 using methylsulfonyl chloride instead of acetyl chloride in step e), white solid, MS (ESI): 422.21 [M+H]+.

Example 4

5-(2-Chloro-4-methylphenyl)-1-(3-chlorobenzyl)-1H-benzo[d]imidazole-7-carboxylic acid

[0121] ##STR00010##

[0122] a) Methyl 5-(2-chloro-4-methylphenyl)-1-(3-chlorobenzyl)-1H-benzo[d]imidazole-7-carboxylate

[0123] In a 25 ml round-bottomed flask, methyl 6-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-4-carboxylate (see Example 2, 150 mg, 474 μmol, Eq: 1) and cesium carbonate (247 mg, 758 μmol, Eq: 1.6) were combined with dimethylformamide (3.5 ml). 3-Chlorobenzyl bromide (97.4 mg, 62.1 μl, 474 μmol, Eq: 1) was added and the reaction was stirred at 75° C. for 3 h. The reaction mixture was poured into 20 ml saturated NaCl solution and extracted with EtOAc (3×50 ml). The organic layers were combined, dried over MgSO.sub.4, filtered through sintered glass, concentrated and dried in vacuo. The crude material was purified by chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM to afford the title compound methyl 5-(2-chloro-4-methylphenyl)-1-(3-chlorobenzyl)-1H-benzo[d]imidazole-7-carboxylate (102 mg, 240 μmol, 50.6% yield), MS (ESI): 425.2 [M+H]+.

[0124] b) 5-(2-Chloro-4-methylphenyl)-1-(3-chlorobenzyl)-1H-benzo[d]imidazole-7-carboxylic acid

[0125] In a 5 ml vial, methyl 5-(2-chloro-4-methylphenyl)-1-(3-chlorobenzyl)-1H-benzo[d]imidazole-7-carboxylate (95 mg, 223 μmol, Eq: 1) and LiOH monohydrate (14.1 mg, 335 μmol, Eq: 1.5) were combined with THF (1.2 ml) and water (600 μl). The reaction mixture was stirred at room temperature for 3 h. For work-up HCl (1M, 335 μl, 335 μmol, Eq: 1.5) was added. The reaction mixture was poured into 20 ml of water and extracted with EtOAc (3×25 ml). The organic layers were combined, dried over MgSO4, filtered through sintered glass, concentrated and dried in vacuo to afford the title compound 5-(2-chloro-4-methylphenyl)-1-(3-chlorobenzyl)-1H-benzo[d]imidazole-7-carboxylic acid (86.6 mg, 204 μmol, 91.5% yield) as white solid, (MS (ESI): 411.19 [M+H]+.

Example 5

5-(2-Chloro-4-methylphenyl)-1-(pyridin-4-ylmethyl)-1H-benzo[d]imidazole-7-carboxylic acid

[0126] ##STR00011##

[0127] The title compound was obtained in comparable yield analogous to the procedure described for Example 4 using 4-(chloromethyl)pyridine hydrochloride instead of 3-chlorobenzyl bromide in step a), white solid, MS (ESI): 378.17 [M+H]+.

Example 6

5-(2-Chloro-4-methylphenyl)-1-(pyridin-3-ylmethyl)-1H-benzo[d]imidazole-7-carboxylic acid

[0128] ##STR00012##

[0129] The title compound was obtained in comparable yield analogous to the procedure described for Example 4 using 3-(chloromethyl)pyridine hydrochloride instead of 3-chlorobenzyl bromide in step a), white solid, MS (ESI): 378.17 [M+H]+.

Example 7

6-(2-Chloro-4-methylphenyl)-3-(pyridin-2-ylmethyl)benzimidazole-4-carboxylic acid

[0130] ##STR00013##

[0131] The title compound was obtained in comparable yield analogous to the procedure described for Example 4 using 2-(chloromethyl)pyridine hydrochloride instead of 3-chlorobenzyl bromide in step a), off-white solid, MS (ESI): 378.100 [M+H]+.

Example 8

5-(2-Chloro-4-methylphenyl)-1-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazole-7-carboxylic acid

[0132] ##STR00014##

[0133] The title compound was obtained in comparable yield analogous to the procedure described for Example 4 using 2-bromo-N,N-dimethylethan-1-amine hydrobromide instead 3-chlorobenzyl bromide in step a), white solid, (MS (ESI): 358.23 [M+H]+.

Example 9

5-(2-Chloro-4-methylphenyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-7-carboxylic acid

[0134] ##STR00015##

[0135] a) Methyl 5-bromo-1-(2-methoxyethyl)-1H-benzo[d]imidazole-7-carboxylate

[0136] In a 25 ml round-bottomed flask, methyl 6-bromo-1H-benzo[d]imidazole-4-carboxylate (250 mg, 903 μmol, Eq: 1) and cesium carbonate (465 mg, 1.43 mmol, Eq: 1.58) were combined with dimethylformamide (8 ml). 1-Bromo-2-methoxyethane (198 mg, 134 μl, 1.43 mmol, Eq: 1.58) was added and the reation was stirred at room temperature overnight. The reaction mixture was poured into 50 ml saturated NaCl solution and extracted with EtOAc (3×75 ml). The organic layers were combined, dried over MgSO.sub.4, filtered through sintered glass, concentrated and dried in vacuo. The crude material was purified by chromatography (silica gel, 12 g, 0% to 80% EtOAc in heptane to afford the title compound methyl 5-bromo-1-(2-methoxyethyl)-1H-benzo[d]imidazole-7-carboxylate (142.6 mg, 455 μmol, 50.4% yield) as white solid, MS (ESI): 313.0, 315.0 [M+H]+.

[0137] b) Methyl 5-(2-chloro-4-methylphenyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-7-carboxylate

[0138] In a 5 ml vial, methyl 5-bromo-1-(2-methoxyethyl)-1H-benzo[d]imidazole-7-carboxylate (50 mg, 160 μmol, Eq: 1), (2-chloro-4-methylphenyl)boronic acid (27.2 mg, 160 μmol, Eq: 1) and potassium phosphate (tribasic) (67.8 mg, 319 μmol, Eq: 2) were combined with dioxane (1 ml) and water (250 μl). The vial was degassed with argon before X-phos (3.81 mg, 7.98 μmol, Eq: 0.05) and tris(dibenzylideneacetone)dipalladium-chloroform adduct (4.13 mg, 3.99 μmol, Eq: 0.025) were added. The vial was closed and the reaction mixture was heated to 110° C. and stirred for 2 h. For work-up the reaction mixture was poured into 20 ml of water and extracted with EtOAc (3×25 ml). The organic layers were combined, dried over MgSO.sub.4, filtered through sintered glass, concentrated and dried in vacuo. The crude material was purified by chromatography (silica gel, 12 g, 0% to 5% MeOH in DCM to afford the title compound methyl 5-(2-chloro-4-methylphenyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-7-carboxylate (41.5 mg, 107 μmol, 66.9% yield) as off-white solid, MS (ESI): 359.21 [M+H]+.

[0139] c) 5-(2-Chloro-4-methylphenyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-7-carboxylic acid

[0140] In a 10 ml round-bottomed flask, methyl 5-(2-chloro-4-methylphenyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-7-carboxylate (38 mg, 106 μmol, Eq: 1) and LiOH monohydrate (6.67 mg, 159 μmol, Eq: 1.5) were combined with THF (0.75 ml) and water (375 μl). The reaction mixture was heated to 65° C. and stirred for 3 h. The reaction was quenched with HCl (0.1M, 159 μl, 159 μmol, Eq: 1.5) poured into 20 ml of water and extracted with EtOAc (3×25 ml). The organic layers were combined, concentrated and dried in vacuo to afford the title compound 5-(2-chloro-4-methylphenyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-7-carboxylic acid (35.9 mg, 96.6 μmol, 91.2% yield) as white solid, MS (ESI): 345.12 [M+H]+.

Example 10

5-(2-Chloro-4-methylphenyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylic acid

[0141] ##STR00016##

[0142] a) Methyl 5-bromo-l-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate

[0143] Methyl 6-bromo-1H-benzo[d]imidazole-4-carboxylate (302 mg, 1.18 mmol, Eq: 1), cyclopropylboronic acid (265 mg, 2.96 mmol, Eq: 2.5) and sodium carbonate (314 mg, 2.96 mmol, Eq: 2.5) were suspended in 1,2-dichloroethane (15 ml). At room temperature a solution of copper(II) acetate (263 mg, 1.42 mmol, Eq: 1.2) and 2,2-bipyridyl (224 mg, 1.42 mmol, Eq: 1.2) in 1,2-dichloroethane (20 ml, prepared at 70° C.) was added dropwise. The reaction mixture was stirred at 80° C. (oil bath temperature) overnight. For work-up the reaction mixture was diluted with dichloromethane and washed with saturated NH.sub.4Cl solution and saturated NaCl solution, successively. The organic layer was dried with Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purifieed by column chromatography (silica gel, 0% to 100% EtOAc in heptane followed by 10% MeOH in CH.sub.2Cl.sub.2) to yield the title compound methyl 5-bromo-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate (16.4 mg, 55.5 μmol, 4.7% yield) as yellow solid, MS (ESI): 295.0, 297.0 [M+H]+.

[0144] b) Methyl 5-(2-chloro-4-methylphenyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate

[0145] Methyl 5-bromo-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate (14.7 mg, 49.8 μmol, Eq: 1) and (2-chloro-4-methylphenyl)boronic acid (12.7 mg, 74.7 μmol, Eq: 1.5) were solved in 1,4-dioxane (800 μL) and water (400 μl). Cesium carbonate (65.6 mg, 199 μmol, Eq: 4) was added and the mixture was degassed by bubbling argon through the mixture (5 min), then 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (2.03 mg, 2.49 μmol, Eq: 0.05) was added. The reaction was stirred in a sealed tube at 90° C. (oil bath-temp.) for 15 min. For work-up the mixture was taken up in EtOAc and washed with saturated NH.sub.4Cl solution and brine successively, the organic layer was dried over Na.sub.2SO.sub.4, filtrated and evaporated. The residue was purified by column chromatography (silica gel, 0% to 100% EtOAc in heptane) to yield the title compound methyl 5-(2-chloro-4-methylphenyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate (12 mg, 35.2 μmol, 70.7% yield) as a colorless oil, MS (ESI): 341.1 [M+H]+.

[0146] c) 5-(2-Chloro-4-methylphenyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylic acid

[0147] Methyl 5-(2-chloro-4-methylphenyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate (12 mg, 35.2 μmol, Eq: 1) was dissolved in THF (500 μl). At room temperature LiOH solution (1M, 105.6 μl, 105.6 μmol, Eq: 3) was added. The mixture was stirred for 2 days at 65° C. For work-up the reaction mixture was diluted with water and extracted two times with diethylether, the organic layers were washed with water and the combined aqueous layers were acidified with HCl (2M, 79.2 μl, 158 μmol, Eq: 4.5) and adjusted to pH3. It was extracted two times with 2-methyltetrahydrofuran and the combined organic layers were dried over Na.sub.2SO.sub.4, filtrated and evaporated to afford the title compound 5-(2-chloro-4-methylphenyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylic acid (10 mg, 30.6 μmol, 86.9% yield) as white solid, MS (ESI): 327.1 [M+H]+.

Example 11

5-(2-Chloro-5-fluoro-4-methylphenyl)-1-ethyl-1H-benzo[d]imidazole-7-carboxylic acid

[0148] ##STR00017##

[0149] The title compound was obtained in comparable yield analogous to the procedure described for Example 9 using ethyl iodide instead of 1-bromo-2-methoxyethane in step a) and (2-chloro-5-fluoro-4-methylphenyl)boronic acid instead of (2-chloro-4-methylphenyl)boronic acid in step b), white solid, MS (ESI): 333.1 [M+H]+.

Example 12

5-(2-Chloro-4-methylphenyl)-1-ethyl-1H-benzo[d]imidazole-7-carboxylic acid

[0150] ##STR00018##

[0151] The title compound was obtained in comparable yield analogous to the procedure described for Example 9 using ethyl iodide instead of 1-bromo-2-methoxyethane in step a), white solid, MS (ESI): 315.1 [M+H]+.

Example 13

5-(2-Chloro-4-methylphenyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-7-carboxylic acid

[0152] ##STR00019##

[0153] The title compound was obtained in comparable yield analogous to the procedure described for Example 9 using 2,2,2-trifluoroethyl trifluoromethanesulfonate instead of 1-bromo-2-methoxyethane and potassium carbonate instead of cesium carbonate in step a), white solid, MS (ESI): 369.1 [M+H]+.

Example 14

5-(2-Chloro-4-methylphenyl)-1-phenethyl-1H-benzo[d]imidazole-7-carboxylic acid

[0154] ##STR00020##

[0155] The title compound was obtained in comparable yield analogous to the procedure described for Example 9 using phenethyl bromide instead of 1-bromo-2-methoxyethane and potassium carbonate instead of cesium carbonate in step a), white solid, MS (ESI): 391.2 [M+H]+.

Example 15

1-Benzyl-5-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazole-7-carboxylic acid

[0156] ##STR00021##

[0157] The title compound was obtained in comparable yield analogous to the procedure described for Example 9 using benzyl bromide instead of 1-bromo-2-methoxyethane in step a), off-white solid, MS (ESI): 377.3 [M+H]+.

Example 16

[0158] Malachite Green Assay to Measure cGAS Activity

[0159] Compounds were tested for cGAS inhibition in a coupled enzymatic assay based on Phosphate detection by Malachite Green. Final assay conditions were 20 mM TRIS pH 7.5 (Applichem), 5 mM MgCl.sub.2 (Sigma) and 0.01% BSA (Sigma) supplemented with 80 μM ATP (Sigma), 80 μM GTP (Sigma) and 100 nM Interferon Stimulating DNA (ISD) (Microsynth). Recombinantly expressed purified human cGAS (residues 161-522) was used at 25 nM.

[0160] All compounds were prepared as 10 mM stock solutions in DMSO and a 16 pt dilution series in DMSO with a dilution factor of 2.5 was prepared. 1 μL of DMSO dilution series was transferred to 32.3 μL reaction buffer, mixed by pipetting up/down, spun for 1 minute at 3000 rpm and was visually inspected for precipitation. 5 μL of 3-fold enzyme stock solution were transferred to an empty 384-well Black/Clear Flat Bottom Polystyrene NBS (Corning) rows 3-24. Rows 1-2 were filled with assay buffer. Plates were spun 10 seconds at 1000 rpm (164×g). 5 μL of compound intermediate dilution was added and mixed by pipetting up/down to rows 3-24. Rows 1-2 were filled with 3.1% DMSO assay buffer. Plates were spun 10 seconds at 1000 rpm (164×g). 5 μL 3-fold Nucleotide/DNA mix was added to all wells to start the reaction. Plates were spun 10 seconds at 1000 rpm (164×g) and incubated for 4 hour at room temperature (RT) in the dark. 5 μL 4 U/mL PPase (Sigma) were added to all wells. Plates spun 10 seconds at 1000 rpm (164×g). 10 μL BioMol green Solution (Enzo Life Sciences) was added to all wells. Plates spun 10 seconds at 1000 rpm (164×g) and incubated 30 minutes at RT in the dark. Absorbance data was collected 620 nm on an EnVision Multilable Reader (Perkin Elmer) and the following measurement settings were used: excitation filter photometric was 620 nm; excitation from the top; measurement height was 1 mm; number of flashes was 30; number of flashes integrated was 1.

[0161] All plates are checked for abnormalities and outliers in the Blank Control (no protein, row 1) and the Neutral Control (no compound, row 2) are excluded using the 3*SD rule. Data was normalized to 0 and 100% by Blank and Neutral Control and each curve was fitted and judged using the 4 parameter logistic equation to determine the IC50 for cGAS inhibition.

[0162] The results of this assay are provided in Table 1. Table 1 provides IC50 values (μM) for cGAS inhibition obtained for particular examples of the present invention as measured by the above-described assay.

TABLE-US-00001 Example IC50 cGAS (μM) 1 1.12 2 2.34 3 1.34 4 2.59 5 0.87 6 2.07 7 1.76 8 2.02 9 3.04 10 4.79 11 1.93 12 2.81 13 3.29 14 1.86 15 2.41

Example A

[0163] Film coated tablets containing the following ingredients can be manufactured in a conventional manner:

TABLE-US-00002 Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg  200.0 mg  Microcrystalline cellulose 23.5 mg  43.5 mg  Lactose hydrous 60.0 mg  70.0 mg  Povidone K30 12.5 mg  15.0 mg  Sodium starch glycolate 12.5 mg  17.0 mg  Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg  350.0 mg  Film Coat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titan dioxide 0.8 mg 1.6 mg

[0164] The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution/suspension of the above mentioned film coat.

Example B

[0165] Capsules containing the following ingredients can be manufactured in a conventional manner:

TABLE-US-00003 Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mg  Maize starch 20.0 mg Talc  5.0 mg

[0166] The components are sieved and mixed and filled into capsules of size 2.

Example C

[0167] Injection solutions can have the following composition:

TABLE-US-00004 Compound of formula (I)  3.0 mg Polyethylene glycol 400 150.0 mg Acetic acid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml

[0168] The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.